TNF-α is an inflammatory cytokine produced from macrophage, macrophage-like cells (kupffer's cell and microglia), neutrophile, basophil, acidophil, lymphocyte, NK cell, LAK cell, mast cell, myeloma cell, fibroblast, astrocyte, keratinocyte and the like. Its deep involvement in the onset pathologies of many diseases has been clarified in recent years, and the possibility of establishing a new treatment method based on the regulation of excessive TNF-α has been reported (Black et al., Annual Reports in Medicinal Chemistry, Vol. 32, pp. 241-250 (1997)).
As regards the relationship between TNF-α and pathology, for example, abnormal production of inflammatory-cytokines, such as TNF-α, interleukin 1β, interleukin 6 and the like, is considered to be the cause of systemic inflammatory response syndromes including sepsis, septic shock and multiple organ dysfunction syndrome (MODS), where neutralization of TNF-α can suppress increase in interleukin 1β and interleukin 6 in blood (Tracey et al., Nature, vol. 0.330, pp. 662-664 (1987)).
Moreover, there is a report stating that insulin resistance induced by obesity is improved in TNF-α deficient animals, suggesting the relationship between TNF-α and non-insulin dependent diabetes mellitus (NIDDM) (Uysal et al., Nature, vol. 389, pp. 610-614 (1997)).
Incidentally, it has been clarified in the field of autoimmune diseases that TNF-α causes disorders of neurocyte and oligodendrocyte, and that TNF-α plays a role of an effecter of neurodegeneration and demyelination (Suzumura, IGAKU NO AYUMI, vol. 185, pp. 931-935 (1998)).
Moreover, detection of a large amount of TNF-α in the synovial fluid of chronic articular rheumatism patients has been also reported (Saxne et al., Arthritis Rheumatism, vol. 31, pp. 1041-1045 (1998)).
Other than the above, involvement of TNF-α has been pointed out as a causative factor of Crohn's disease, fulminant hepatitis, cachexia, bone resorption disorder, cardiac infarction, allergic disease and adult respiratory distress syndrome.
TNF-α is closely related to the onset and aggravation of various diseases, and therefore, suppression of the action of TNF-α is considered to afford treatment of such diseases.
At present, steroidal hormone preparations and non-steroidal anti-inflammatory drugs have been applied to some of the inflammatory diseases. However, harmful side effects may be induced, because the sites of action thereof range widely and the TNF-α suppressive action is not a specific one. Particularly, the side effects of steroids pose medical problems. In addition, there is an in vitro experiment report indicating that pharmaceutical agents having a phosphodiesterase inhibitory action suppress TNF-α production. However, the effect thereof in the body is very weak and clinical application is considered to be difficult (Suzumura, mentioned above (1998)). Furthermore, a treatment using a TNF-α antibody or soluble TNF-α receptor, which is a peptidic polymer compound, shows fine clinical results in chronic articular rheumatism, Crohn's disease and the like, but the treatment effect is not long-lasting except in some patients.
In view of the present situation, the development of a pharmaceutical agent for the prophylaxis or treatment of various diseases considered to be caused by abnormal production of TNF-α, which specifically suppresses TNF-α production and which shows a superior treatment effect in the body has been demanded.
However, as heterocyclic compounds represented by the formula (I) to be mentioned later, for example, J. Am. Chem. Soc., 81, pp. 2456-2464 (1959) and J. Org. Chem. 24, pp. 963-964 (1959) describe compounds of the following formulas
but do not describe bioactivity. In addition, Tetrahedron 30(16), pp. 2791-2796 (1974) describes compounds of the following formulas
but does not describe bioactivity. Moreover, Indian J. Chem, 5(10), pp. 464-466 (1967) describes compounds of the following formulas
and a compound of the following formula
but does not describe bioactivity.
In addition, Bull. Chem. Soc. Jpn., 46, pp. 1801-1803 (1973) describes compounds of the following formulas
but again, does not describe bioactivity. In other words, use of a heterocyclic compound represented by the formula (I) as a pharmaceutical agent is not reported.